CA1336777C - Dextro-rotatory enantiomer of methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate, a process for its preparation and the pharmaceutical compositions containing it - Google Patents

Dextro-rotatory enantiomer of methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate, a process for its preparation and the pharmaceutical compositions containing it

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CA1336777C
CA1336777C CA000558412A CA558412A CA1336777C CA 1336777 C CA1336777 C CA 1336777C CA 000558412 A CA000558412 A CA 000558412A CA 558412 A CA558412 A CA 558412A CA 1336777 C CA1336777 C CA 1336777C
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rotatory
dextro
acetate
tetrahydro
chlorophenyl
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Alain Badorc
Daniel Frehel
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Sanofi Aventis France
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
    • C07J41/0061—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives one of the carbon atoms being part of an amide group

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Abstract

The dextro-rotatory enantiomer of formula:

Description

The present invention relates to the dextro-rotatory enantiomer of methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chorGphenyl)-acetate, a process for its preparation and pharmaceutical compositions containing it.
The compound of the invention corresponds to the following formula (l~:

COOC~3 ~ ~ ~ (I) in which the C is an asymmetric carbon atom. In fact, this formula 15 represents both the dextro-rotatory molecule cl~med as well as its levo-rotatory enantiomer. The racemic mixture corresponding to this formula was described in the French patent application published under the No. 2 530 247.
Hereafter the dextro-rotatory enantiomer claimed according to the invention will be designated by Id and the levo-rotatory enantiomer by Il.
It is known that the optical rotatory power of a compound depends on the solvent in which it is measured and on its concentration in this solvent. The optical rotatory power of the dextro-rotatory isomer according to the invention is positive in methanolic solution.

Z5 In an unexpected manner only the dextro-rotatory enantiomer Id exhibits a platelet aggregation inhibiting activity, the levo-rotatory enantiomer Il being inactive. Moreover, the inactive levo-rotatary enantiomer Il is the less well tolerated of the two enantiomers.
The invention also relates to the addition salts of the compounds 30 of formula (Id) with pharmaceutically acceptable mineral or organic acids.
The compound (Id) is an oil whereas its hydrochloride exists as a white powder. The oily products are usually difficult to purify and it is preferable to use for the preparation of pharmaceutical compositions crystalline products which can usually be purified by recrystallization.

However, it has been observed in the present case that some of the salts of compound (Id) usually precipitate in an amorphous form and/or that they are hygroscopic, a property which makes them difficult to handle on an industrial scale. Thus, the salts of carboxylic and sulfonic acids classically used in pharmacy have been prepared, acids such as acetic, benzoic, fumaric, maleic, citric, tartaric, gentisicj methane-sulfonic, ethanesulfonic, benzenesulfonic and laurylsulfonic acids as well as the salts of dobesilic acid (m.p =70 C) and para-toluenesulfonic acid (m.p.= 51 C), the purification of which proved to be difficult.
Among the mineral and organic acid salts of the dextro-rotatory isomer of the compound of Forrllula ~Id) salts have been found which crystallize easily,al~e not hy~roscopic and are sufficiently water-soluble as to make their use as active medicinal principles particularly advantageous.
The present invention thus relates more particularly to the hydrogen sulfate, the taurocholate and the hydrobromide of the dextro-rotatory enantiomer of methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chloropheny~-acetate.
These salts are prepared in a standard manner by the action of the corresponding acid on the base in solution in a solvent fi-om which they precipitate spontaneously or after addition of a non-solvent of the salt.
The dextro-rotatory isomer of methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate can be prepared by forming the salt of the racemic compound with an optically active acid in a solvent, repeated recrystallizations of the salt until a product of constant optical rotatory power is obtained, followed by the liberation of the dextro-rotatory isomer from its salt by a base; if required, a salt is formed between the dextro-rotatory isomer and a pharmaceutically acceptable acid.
The optically active acid may advantageously be levo-rotatory campho r-lo-sulfonic acid.
One and the same solvent may be used for salt formation and recrystallization: acetone is ideally suited in this case.

~ .

_3 _ 1 336777 The chiral, levo-rotatory camphor-10-sulfonic acid of formula (II1) is allowed to react in an inert solvent with the racemic mixture of formula (I) according to the following reaction scheme:

COOCH 3 H3 ( (II levo-rotatory) Salt formation may be carried out in solvents such as alcohols, ketones, dimethylformamide. The salt precipitates spontaneously or is isolated by salting out or evaporation of the solvent. A mixture of two diastereoisomers of formula (IIIa) is formed. By repeated recrystallizations from a solvent such as acetone the precipitate is enriched in the salt of the dextro-rotatory isomer of compound (I). After each recrystallization the optical rotatory power [a]2D0 of the precipitate is measured at 20C in methanol at a concentration varying between 1.5 and 2 g/100 ml. When the [a~D20 stops increasing the base of formula (ID) is liberated from the salt (IIIa) by the action of a base such as sodium or potassium hydrogen carbonate in aqueous media at temperatures varying between 5C and 20C. Evaporation of the filtrate of the first recrystallization IV after the crystals of the precipi-tated salt (IIIa) have been filtered off, gives a mixture enriched in the salt of (I1) enantiomer. The basification of this mixture of diastereoisomeric salts with a weak base such as sodium or potassium hydrogen carbonate in aqueous solution at temperatures varying between 5C and 20C leads to a mixture of the two enantiomers (Id) plus (I1) enriched in the levo-rotatory enantiomer (I1).
This mixture (Id) + (I1) enriched in enantiomer (I1) is allowed to react with dextro-rotatory camphor-10-sulfonic acid which will be designated as (IId) in a solvent according to the following reaction scheme:

with ~I1) in exces~ ~ ~ (lIIb) (II dextro-r~tatory) The crystalline mixture of diastereoisomeric salts (IIIb) obtained is recrystallized from acetone until the optical rotatory power [a]D20 of the precipitate remains constant.
As previously mentioned the optical rotatory power [a]2D0 of the diasteroisomeric salt (IIIb) is determined after each recrystallization.
The liberation of the stereoisomer (I1) from its salt is carried out in a standard manner, like that for compound (Id). Levo-rotatory camphor-lo-sulfonic acid (II1) may be obtained from commercially available ammonium camphor-10-sulfonate of formula (V) according to the reaction scheme:

-~ 336777 ~H3 ion exchange (~ 3 S03H
3 ~SO~ NH4 Q ~ ~3C ~

(V) (IIl) An aqueous solution of the ammonium salt (V) is chromatographed on an Amberlite* IRN-77 resin. After lo lyophilization of the eluate camphor-10-sulfonic acid of formula (II1) is recovered.
The entire sequence of the process is shown schematically below:

(I) + (lIt) acétone make alkaline(Id) + (It) (Illa) + ¦ Solution (IV)¦

aqueous NaHC03(It) in excess + (lld) acétone 2 0 recrystallisation ~ acétone ~

(Illa) Pure (Illb) recrystallisation make alkaline with acetone aqueous NaHC03 ~

(Illb) pure ~ make alkaline vith dextro-lot~ y aqueous NaHC03 enantiomer V

~1 3 levo-rotatory enantiomer * trade name X

Each of the pure enantiomers (Id) and (Il) may be converted into a salt by means of the standard methods: for example,the hydrochlorides are prepared by the addition of a solution of'hydrogen chloride gas in diethyl ether to a solution of (Id) or (Il) in diethyl ether.
5 Determination of the enantiomeric purity of the dextro-rotatory (Id) and levo-rotatory (Il) enantiomers Two methods have been used:
- proton NMR spectroscopy with the addition of a chiral rare earth - high pressure liquid chromatography using a chiral stationary phase.
a) Proton NMR spectroscopy with the addition of a chiral rare earth The enantiomeric purity (optical purity) was determined by H 60 MHz NMR
spectroscopy in the presence of a rare earth chiral complex according to the method described by G.M. WHITESIDES et al. (J. Am. Chem. Soc. 1974, 96, 1038).
In the racemic product (I), the hydrogen attached to the asymmetric centre in the ~ position to the ester function appears as a singlet (chemical shift ~ - 4.87 ppm in CDC13 as solvent. The addition of the rare earth 20 complex Eu(tfc)3 /tris 3-(trifluoromethyl hydroxymethylene)-d-camphorato europium (III)/ to the probe containing a solution of the racemate (I) in CDCl3 leads to the resolution of the initial singlet into two, well-separated singlets corresponding to the proton of each of the two enantiomers (Id) and (Il). When the molar ratio of rare earth complex/compound (I) = 0.4, the separation between the two singlets is about 6 Hz.
With each of the two enantiomers prepared~(Id) and (Il), the same procedure was used as for the racemate (I). The smaller chemical shift corresponds to the proton of the dextro-rotatory enantiomer (Id) and the larger chemical shift to the levo-rotatory enantiomer (Il).
30 The precision of the method was determined by comparing the H (60 MHz) NMR
spectra obtained with and without addition of the rare earth complex for each of the two enantiomers (Id) and (Il) in the pure state or as mixtures containing increasing quantities of one of the enantiomers. It was observed that it was possible to detect easily more than 5% by weight of one enantiomer in the presence of the other.

; ` ~ 7 ~ 1 3367~7 b) High pressure liquid chromatography using a chiral stationary phase The study was conducted with a liquid chromatograph HP-1084*using a W detector at 215 nm. The chiral stationary phase was DEAE silica (10 microns) onto which was grafted alpha-l acid glycoprotein (0.~ x 100 mm) 5 (ENANTIOPAC R-LKB). The mobile phase consisted of an aqueous phosphate buffer mixture 8 mM (NaH2P04/Na2HP04) containing n.l M of NaCl, adjusted to pH = 7.4, and 15% of isopropanol (v/v). The flow rate was fixed at 0.3 ml/minute and the temperature of the column was maintained at 18-20 C.
Under these conditions, the dextro-rotatory enantiomer (Id) has a retention lO time of 45 minutes and the levo-rotatory enantiomer (Il) has a retention time of 35 minutes.
The precision of the determination of the optical purity of the two enantiomers was estimated by chromatographing each of the two enantiomers (Id) and (Il) prepared either alone or as a mixture containing increasing 15 amounts of one of the enantiomers. It was observed that it was easy to detect:
- 2% (weight/weight) of enantiomer (Id) in enantiomer (Il) - 4% (weight/weight) of enantiomer (Il) in enantiomer (Id).
Under these conditions it may be concluded that the optical purity of the 20 two enantiomers (Id) and (Il) obtained according to the exa~?les is at least equal to 96% for the dextro-rotatory enantiomer (Id) and at least equal to 98% for the levo-rotat~ry enantiomer (Il).
The following examples are non-restrictive and are presented to illustrate the present invention.
25 EXAMPLE 1 - Salts of dextro-rotatory methyl-alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate.
a) levo-rotatory camphor-10-sulfonic acid A column of Amberlite IRN-77 resin is prepared and treated by passing 1 N hydrochloric acid through it and then by washing this column of 30 acidifed resin abundantly with water. Levo-rotatory ammonium camphor-10-sulfonate is dissolved in a minimum of water and applied to the column of resin previously prepared. Elution is carried out with water. The eluted fractions containing the acid are lyo~hilized.20 White crystals, m.p. = 198 C; _~--/ D = -20.53 (c = 2.075 g/100 ml 35 water).

* trade-marks 2, b) Camphor-10-sulfonic acid salt of methyl alpha -5(4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate (SR 25990 B).
32 g (0.0994 mole) of racemic methyl alpha ~5(4,5,6,7-tetra-hydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate are dissolved in 5 150 ml of acetone. 9.95 g (0.0397 mole) of levo-rotat camphor-10-sulfonic acid monohydrate are added. The clear solution is left to stand at room temperature. After 48 hours some crystals have formed. The reaction mixture is concentrated to 50 ml and left to stand at room temperature for 24 hours. The crystals obtained are filtered off, washed lO with acetone and dried (yield: 55% on the basis of the starting racemate).
White crystals, m.p. = 165C, _~ /D0 = 1 24.67 (c . 1.58 g/100 ml;
methanol).
The crystals obtained above are redissolved in the minimum of boiling acetone (50 ml). The crystals obtained after cooling are 15 filtered off, washed with acetone and dried (yield: 88%).
White crystals, m.p. = 165 C, _bC/ 20 = t24.75 (c - 1.68 g/100 ml;
methanol). D
c) Dextro-rotatory methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chorophenyl)-acetate.
12 g (0.022 mole) of the pure product obtained in b) are dissolved in a ~;n; Im of water. After cooling to 5 C, the aqueous solution obtained is made alkaline with a saturated aqueous solution of sodium hydrogen carbonate. The alkaline aqueous phase is extracted with dichloromethane.
The organic extracts are dried over anhydrous sodium sulfate. On 25 evaporation of the solvent a colourless oil is obtained (quantitative yield). Oil, _c~/ DO _ ~51.52 (c _ 1.61 g/100 ml; methanol).
d) The hydrochloride of methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate (dextro-rotatory) (SR 25990 A).
7 g (0.0228 mole) of dextro-rotatory methyl alpha-5 (4,5,6,7-tetra-30 hydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate are dissolved in 100 ml of diethyl ether. 30 ml of a solution of 1 N HCl in diethyl ether are added and the crystals obtained are filtered off. The crystals are washed with diethyl ether and dried (yield: 94~).
White crystals, m.p. _ 117 C, _~/D - ~62.23 (c - 1.82 g/100 ml;
35 methanol).

e) The hydrogen sulfate of dextro-rotatory methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate (SR 25990 C).
800 ml of a saturated aqueous solution of sodium bicarbonate are added to a suspension of 200 g of SR 25990 B in 800 ml of dichloro-methane. After vigorous shaking, the organic phase is separated, dried over sodium sulfate and the solvent is removed under reduced pressure.
The residue is dissolved in 500 ml of ice-cold acetone and 20.7 ml of concentrated sulfuric acid (93.64%, d - 1.83) are added drop-wise.
The precipitate formed is isolated by filtration and washed with 1,000 ml of acetone, then dried in a vacuum oven at 50C.
139 grams of analytically pure white crystals are thus obtained with a melting point of 184 C. Empirical formula: C16 H16ClN02S
.H2S04 _~-/ D = ~55.10 (c = 1.891 g/100 ml; methanol).
f) The hydrobromide of dextro-rotatory methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate (SR 25990D).
150 ml of an aqueous solution of sodium bicarbonate are added to a suspension of 20 g of SR 25990 B in 200 ml of dichloromethane. The residue obtained after separation of the organic phase, drying and evaporation of the solvent is dissolved in 150 ml of diethyl or diisopropyl ether, and 4.4 ml of a 48% (wt/v) aqueous solution of hydrobromic acid are added drop-wise. The precipitate formed is isolated.
After drying, 14.4 g of crystals are obtained with a melting point of 111C (yield 99%).
13.4 g of these crystals are recrystallized from a mixture of isopropyl ether (100 ml) and isopropanol (150 ml) to give 10.2 g of analytically pure hydrobromide: m.p. _ 140 C; empirical formula: C16H16 CLN02S-HBr -~ t D s ~59.23 (c . 2.09 g/100 ml; methanol).
g) The taurocholate of dextro-rotatory methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate (SR 25990E).
The sodium salt of taurocholic acid is chromatographed on Amberlite IRN-77 resin by eluting with water. The fractions obtained are lyophilized.

3 g (0.0054 mole) of SR 25990B are treated with a saturated aqueous solution of sodium bicarbonate and the mixture is extracted with dichloromethane. The organic phase is separated, dried over sodium sulfate and evaporated to dryness. The free base obtained is taken up in 30 ml of isopropanol; 2.8 g (0.0054 mole) of taurocholic acid dissolved in 100 ml of isopropanol are added to this solution. The mixture is stirred overnight at room temperature, then evaporated to dryness. The residue solidified on being triturated with ether. 3.5 g of beige crystals are obtained. m.p. _ 120 C _~ / D ~ =39 53 (c - 1.791 g/100 ml of lO methanol). C16H16ClNO2S.C26H45NO7S; C, H, N analyses in agreement with theory.

EXAMP~E 2 - Salts of levo-rotatory methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate.
a) Salt of d-camphor-10-sulfonic acid (SR 25989 B) After separation of SR 25990 B in Example l-b the solvent is evaporated from the acetone filtrate obtained.
The residue is taken up in water and diethyl ether. The ethereal phase is decante~. The aqueous phase is cooled to 5C and made alkaline with a saturated aqueous solution of sodium bicarbonate. The aqueous alkaline phase is extracted with diethyl ether. The ethereal extracts are pooled and dried over anhydrous sodium sulfate.
On evaporation of the solvent an oil is obtained which is purified by filtration through a bed of silica (eluant: diethyl ether).
25 A colourless oil is recovered consisting of a mixture of about 65% of the levo-rotatory enantiomer and 35% of the dextro-rotatory enantiomer, proportions determined by means of H (60 MHz) NMR spectroscopy after the addition of a chiral, rare earth complex.
16.66 g (0.0517 mole) of the mixture thus obtained are dissolved in 70 ml of acetone. 7.77 g (0.0310 mole) of dextro-rotatory camphor-10-sulfonic acid monohydrate are added. The homogeneous mixture is left to stand overnight at room temperature. The crystals obtained are filtered off, washed with acetone and dried (yield: 44% based on the mixture).

._ - 11 1 3 3 6 7 7 7 The crystals obtained are dissolved in a minimum of refluxing acetone (60 ml). The precipitate obtained on cooling to room temperature is filtered off, washed with acetone and dried. White crystals, m.p. =
167C, /0~/ DO _ -24.85 (c ~ 1.79 g/100 ml; methanol).
b) Levo-rota~ry methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate.
11.3 g (0.0204 mole) of the camphor-10-sulfonate obtained in a) are dissolved in a minimum of water. The aqueous solution obtained is cooled to 5 C and made alkaline with a saturated aqueous solution of sodium hydrogen carbonate. The alkaline aqueous phase is extracted with dichloromethane. The organic solution is dried and the solvent ls evaporated. A colourless oil is isolated (quantitative yield).
Oil _~-/ D - -50.74 (c _ 1.58 g/100 ml; methanol).
c) The hydrochloride of levo-rotatory methyl alpha-5 (4,5,6,7-15 tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate (SR 25989 A).
Prepared according to the method described in Example 1~).
Yield: 94%.
White crystals, m.p. , 117 C, _CC_/ D = -62.56 (c ~ 1.80 g/100 ml;
methanol).
d) The hydrogen sulfate of levo-rotatory methyl-alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate (SR 25989 C).
70 g (0.126 mole) of the camphor sulfonate SR 25989 B obtained are treated as described in a) above with a saturated aqueous solution of sodium bicarbonate in the presence of dichloromethane. The organic phase is separated, dried over sodium sulfate and evaporated to dryness. The residue is taken up in 300 ml of acetone and 7.2 ml (0.126 mole) of concentrated sulfuric acid are added drop-wise. After being stirred the crystals formed are filtered off and washed with acetone. 47.8 g of white crystals are obtained. m.p. = 182C _ ~ / D ~ -51.61 (c = 2.044 g/100 ml;
methanol). The analyses (C,H,N) are in agreement with theory.

PHARMACOLOGICAL STUDY
The platelet aggregation inhibiting activity and the toxicity of these new compounds was compared to those of the racemic mixture described in the French patent No. 82.12599 (Publication No. 2 530 247)~pllhli~he~ on January 20, 1984.

A description will now be given of the results of this study which demonstrates another advantage of the invention, namely that the salts of the dextro-rotatory isomer have a better therapeutic index than the salt of the racemic mixture; in fact, the levo-rotatory isomer 5 exhibits almost no platelet aggregation inhibiting activity and its toxicity is markedly higher than that of its dextro-rotatory homologue.
The platelet aggregation inhibiting activities and the antithrombotic activities of the compounds were studied in the rat by standard methods.
The activity on the aggregation of platelets induced by ADP or collagen was determined ex-vivo.
The products dissolved in ethanol (200 mg/ml) and diluted in water containing gum arabic (5~ - wt/v) were administered by the oral route to groups of five female rats of the CD-COBS strain, weighing 250-300 g, 15 in amounts of 10 ml of suspension per kilogram two hours before blood samples were taken.
The blood samples were taken from animals anesthetized with diethyl ether by puncture of the abdominal aorta and placed over a 3.8% aqueous solution of sodium citrate (1 vol/9 volumes of blood). The 20 platelet-rich plasma was then isolated by centrifugation at 200 g for lO
minutes.
Aggregation is induced by the addition of 2 ~ul of aggregating solution to 400 ~ul of platelet-rich plasma. The aggregating solutions used were: a 500 juM aqueous solution of ADP marketed by Boehringer Mannheim 25 (final concentration 2.5 ~M), and a solution of collagen marketed by Sigma (type 1) at a concentration of 0.25 g/100 ml in 3~ acetic acid (v/v) (final concentration 12.5 lug/ml).
The aggregation of the platelets was monitored as described in the method by G.V.R. Born in Nature 194, p. 927 (1967) using a Coultronics 30 aggregometer at a temperature of 37C and agitation of 900 rpm.
For aggregation with ADP, the ayy~ey~,e~er generates a curve r~e~l~spl~l ing a platelet ayy~eydLion as measured by a change in optical density. m e h~;~ht of this curve is ~ef;n~ as the height of ayyleyaLion.
The ~e,~. dge of ayy~eydLion is the relation between the ayy~eydLion height 35 measured and the height corr~3r~ to 100% ayyr~ydLion x 100. The ~ nl~ge of inhibition is determ med by the relation :

Control aggregation height - produced aggregation height x 100 Control aggregation height The results obtained for the aggregation with ADP for the hydrochloride of the racemic mixture (PCR 4099), the hydrogen sulfates of the dextro-rotatory (SR 25990 C) and levo-rotatOry (SR 25989 C) isomers on the one hand,and for PCR 4099 and the hydrochlorides of the dextro-rotatory (SR 25990 A) and levo-rotatory (SR 25989 A) on the other, are shown in Table I; they demonstrate that the levo-rotatory isomer is inactive and that the dextro-rotatory isomer is at least as active as the racemate.

~_ 1 3 3 6 7 7 7 TABLE

____________________________ ________ ___________________ PRODUCT DOSE aUANTITY Z AGGREG ~ tNH~- p~
mg/Kg ofbase ATION 8rTrON
p o administered _______________ _____ _ _ ___ ________ ________________ Controls ~2,4 ~/-1,5 PCR 4099 4,487,8~29,8 /-2,4 30 0,01 (rac~m ate) 8,97 7.69 17,2 ~/-2,2 59 0,001 17,915 ~811,1 ~/-2,3 74 0,001 SR 25989C 2015,3841,0 ~/-1,5 3 n. s 4030,7637,1 ~/-1,7 13 n. s SR 25990C 1,250,9639,4 ~/-1,3 7 n.s 2,51,9228,4 /-2,3 33 0,01 53,841~,0 /-1,6 67 0,001 107,698,5 /-1,6 80 0,001 ========================================== ==_=,=,======_ Controls 33,~ ~/-2,3 SR 25990E 10 3,84 9,6 ~/-3 72 0,001 20 7,69 4 ~/-1,6 88 0,001 =====================:=============___===================
AGGREGATION
HEIGHT
Contro;s 103 ~/-5 PCR ~O99 2,52,1486 ~/-5 17 0,05 ~racemate) 5 4,28 72 ~/-a 30 0,05 12,510,7132 /-9 69 0,001 SR 259~9A 25 22,46 101 ~-1 2 n.s SR 25990A 2,5 2,25 67 /-7 35 0,01 5 ,~9 26 /-5 75 0,001 12,511,2319 ~ 82 O,001 2522,~611 /-1 ag 0,OO1 _________________________________________________________ * mean of results +/- standard error of the mean (SEM) ** Student test *** aggregation height in mm : mean +/- SEM (n=5) n.s. not significant For the aggregation with collagen, the percentage of inhibition is the difference of the slopes of the curves r~? resentina the variation of theoptical density as a function of time for the control and the product to be tested divided by the slope for the control multiplied by 100. The results shown in Table II demonstrate again that only the dextro-rotatory isomer is active whereas the salts have comparable activities.

... . .

PQODUCT DOSE OUANrIrY SLOPE Z INHI- P~
mg/Kg of base 6IrION
p O administered __ _ __ _ _ ___ __ ________ Controls ~.8 ~/-0.3 PCR ~099 ~.~83,8~ 3,6 ~/-0,2 25 O.OS
(racemate) 8,977,69 2,7 ~/-0,3 4~ 0.01 17.915,38 1,5 ~/-0,3 69 0,001 SR 25989C 2015,33 ~,3 ~/-0,2 10 n.s ~030,76 ~,0 ~/-0,2 17 n.s SR 25990C 1,250,96 ~,5 ~/-0,3 6 n. s 2,51,92 ~ /-0,2 15 n . s S3,84 2,3 ~/-0,1 52 0,001 107,69 1,7 ~/-0,3 65 0,001 ============================__======,==========_=====
Controls 3,5 ~/-0,1 SR 25990E 10 3,84 2,1 ~/-0,5 ~0 0,05 20 7,69 1,~ ~/-0,4 60 0,01 =========================================================
Controls3,97 ~/-0,29 PCR ~099 2,52,14 3,13 ~/-0,33 21 n.s Iracem ate) 5~,28 2,9~ ~/-0,34 26 O,OS
12,510,71 2,19 ~/-0,42 ~5 0,01 SR 2S969A 2522,~6 ~,32 ~/-0,29 10 n.s SR 25990A 2,52,25 3,05 /-0,19 23 O,OS
5~,~9 1,2~ ~/-0,22 69 0,001 12,511,23 0,~6 /-0,1~ 78 0,001 2522,~6 0,7~ ~/-0,1~ 81 0,001 _________________________________________________________ *"~ Student test n.s. not significant The antithrombotic activity of these compounds has also been studied in the test of venous thro~bosis on a screw thread described by Kumada T. et al. in Thromb. Res 18 p. 189 (1980).
Female rats of the same type as those previously described, in groups of 10 ~ni~ , were anesthetized with diethyl ether and their vena cava was isolated after abdominal incision.
A metallic screw thread 21 mm long consisting of a dentist's drill, marketed by Dyna (France) size No. 30, was introduced into the lumen of this vein just below the renal bifurcation descending towards the lO iliac veins, without damaging the wall; 19 to 20 mm of the length of the screw thread are implanted and the r~ining 1 mm protudes through the closed stomach into the exterior.
The thrombi formed rapidly and five hours later, under pentobarbital anesthesia, the abdomen is reopened and ligatures are placed above and below 15 the screw thread which is withdrawn after longitudinal incision of the vein and the isolated thrombus is weighed.
The results which are presented in Table III show that the levo-rotatory isomer is inactive in this test, in contrast to the dextro-rotatory isomer and the racemate.

TABLE III

_____________________ __________________________ _______ PROOUCT DOSE ~U~NrITY WEIGHT of V~RI~ION P~
mg/Kg of base thrombl ~ Z
P . O
admin.
__ _ ______________ __ _ _____________________________ Controls 3 9 ~/ o 3 PCR ~099 ~ ~3 8~ 2.17 ~/-0 2~ ~ 0 001 (rac~mate) 9 977 69 1 39 ~/-0 15 6~ 0 001 17 915 3B 1 00 ~/-0 19 74 0 001 SR 259~9C ~030 76 ~ 17 ~/-0 ~2 -7 n.s SR 25990C 1 250 96 3 11 ~/-0 32 20 n.s 2 51 92 2 29 ~/-0 22 ~1 O.Ol 5 3 84 1 71 ~/-0 2~ 56 0,01 10 7 69 1 26 ~/-0 19 67 D_Ol 2015 3a 1 20 ~/-0 13 69 0,01 ========================================,================
Controls 3 ~9 ~/-0 36 SR 25990E 10 3,~ /-0,15 60 0 001 7 69 1 19 ~/-0 15 6~ 0 001 ______________________________ __________________________ ~ = weight of thrombi in mg +/- standard error of the mean P = U test of Kruskal - Wallis For the toxicological study, the compounds were administered by the oral route in the form of a suspension in the same volume of water made up to 10% (wt/v) with gum arabic to groups of lO fasted female rats of the Sprague Dawley strain weighing 120 to 135 grams.
The number of dead animals was determined 14 days after the a~nlstration of the compound under study. The lethal doses thus determined, expressed in-weight of the salt administered, are presented in Table IV;
these results show on the one hand that the toxicity of the racemic mixture is similar to that of the levo-rotatory isomer whereas the dextro-rotatory isomer is markedly less toxic, and,on the other hand, that the toxicity depends on the nature of the acid used to form the salt.

.~ -- 19 --~ 1 336777 TABLE IV

____ _______________________ ( ~ DOSE
____ ______ ____________________ ____________________ . __ PCR ~099 1318 1615 1979 2000 ~racem~te) (1~8-17~7) ~ 3-1797~
SR 25990 A 3055 ~316 6137 5000 (3569-5705) SR 25990 C 2257 2591 297~ ~000 (2372-2805) SR 25990 D 263~ ~26a 691~ SOOO
(35~1-6012) _________________________________________________________ ( ) = confidence interval - 20 ~

The pharmacological study just presented has demonstrated the interesting inhibitory properties towards platelet aggregation of the compound Id and the absence of any activity of its isomer Il.
The medicine of the invention can be made available for oral administration in the form of tablets, sugar-coated tablets, capsules, drops, granules or a syrup. It can also be made available for rectal administration in the form of suppositories or for parenteral administration in the form of an injectable solution.
Each unit dose contains advantageously from 0.001 g to 0.100 g of the derivative of the invention, and the daily doses to be administered may vary from 0.001 g to 0.500 g of active ingredient dependin~ on the age of the patient and the severity of the disorder to be treated.
Some pharmaceutical formulations of the medicine of the invention will be given below as non-restrictive examples.
1) Tablets Active ingredient .0O.... 0.010 g Excipient: lactose, powdered sugar, rice-starch, alginic acid, magnesium stearate 20 2) Sugar-coated tablets Active ingredient ......... Ø005 g Excipient: magnesium stearate, maize starch, gum arabic, shellac, white sugar, glucose, white wax, carnauba wax, paraffin, cochineal.
3) Capsules Active ingredient ......... Ø025 g Excipient: magnesium stearate, maize starch, lactose.

30 4) Injectable solution Active ingredient ......... 0.050 g Isotonic saline q.s.p. 3 ml 5) Suppositories Active ingredient ...Ø. 0.030 g Semi-synthetic triglycerides q.s.p. l suppository.

- 2l -` _ 1 336777 On account of its interesting inhibitory properties towards platelet aggregation and its interference in the mechanism of formation of arterial and venous thromboses, the medicine of the invention can be usefully administered in the treatment and prevention of platelet S disorders due to extracorporeal blood circuits or the consequence of complications in atheroma.

Claims (11)

1. Dextro-rotatory isomer of methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chloro-phenyl)-acetate and its pharmaceutically acceptable salts.
2. Hydrochloride of the dextro-rotatory isomer of methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate.
3. Hydrogen sulfate of the dextro-rotatory isomer of methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate.
4. Hydrobromide of the dextro-rotatory isomer of methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate.
5. Taurocholate of the dextro-rotatory isomer of methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate.
6. Process for the preparation of the compound according to claim 1, comprising the formation of a salt of racemic methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate with an optically active acid in a solvent, repeated recrystallizations of the salt are carried out until a product of constant optical rotatory power is obtained, then the dextro-rotatory isomer is liberated from its salt by a base and, if desired, salt formation is carried out with a pharmaceutically acceptable acid.
7. Process according to claim 6, comprising levo-rotatory camphor-10-sulfonic acid as the optically active acid.
8. Process according to claim 6, comprising the performance of recrystallizations from acetone.
9. Process according to claim 6, comprising the formation of a salt in acetone.
10. A pharmaceutical composition comprising an effective amount of a compound according to claim 1, as active ingredient, in admixture with a pharmaceutically acceptable carrier.
11. Composition according to claim 10, comprising unit doses containing from 0.001 g to 0.100 g of active ingredient.
CA000558412A 1987-02-17 1988-02-08 Dextro-rotatory enantiomer of methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate, a process for its preparation and the pharmaceutical compositions containing it Expired - Lifetime CA1336777C (en)

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FR8702025A FR2612929B1 (en) 1987-02-17 1987-02-17 DEXTROGYRE ENANTIOMER OF 1A- (TETRAHYDRO- 4,5,6,7 THIENO (3,2-C) PYRIDYL-5) (2-CHLORO-PHENYL) -METYL ACETATE, PREPARATION METHOD THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING IT
FR878716516A FR2623810B2 (en) 1987-02-17 1987-11-27 ALPHA SALTS- (TETRAHYDRO-4,5,6,7 THIENO (3,2-C) PYRIDYL-5) (2-CHLORO-PHENYL) -THETHYL ACETATE DEXTROGYRE AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME
FR8716516 1987-11-27

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